Original Research: Influence of okadaic acid on hyperphosphorylation of tau and nicotinic acetylcholine receptors in primary neurons

Abstract

The aim of the study was to investigate the influence of hyperphosphorylation of tau induced by okadaic acid on the expression of nicotinic acetylcholine receptors and the neurotoxicity of b-amyloid peptide. Primary cultures of neurons isolated from the hippocampus of the brains of neonatal rats were exposed to okadaic acid or/and Ab . Tau phosphorylated at Ser404 and Ser202, and the protein expressions of a7, a4 and a3 nAChR subunits were quantified by Western blotting, and their corresponding mRNAs by real-time PCR. Superoxide dismutase activity was assayed biochemically and malondialdehyde by thiobarbituric acid-reactive substance. As compared to controls, phosphorylations of tau at Ser404 and Ser202 in the neurons were elevated by exposure to 20 nM okadaic acid for 48 h but not by 1 or 2 mM Ab 1-42 . Treatment with 20 nM okadaic acid or 1 mM Ab 1-42 for 48 h resulted in the reduced a7, a4 and a3 proteins, and a4 and a3 mRNAs, as well as the decreased activity of superoxide dismutase and the increased malondialdehyde. Okadaic acid and Ab 1-42 together caused more pronounced changes in the expressions of a7 and a4, superoxide dismutase activity and lipid peroxidation than either alone. When pre-treatment with vitamin E or lovastatin, the neurotoxicity induced by okadaic acid was significantly attenuated. These findings indicate that hyperphosphorylation of tau induced by okadaic acid inhibits the expression of nicotinic acetylcholine receptors at both the protein and mRNA levels, as well as enhances the neurotoxicity of b-amyloid peptide.

Differential Hyperphosphorylation of Tau-S199, -T231 and -S396 in Organotypic Brain Slices of Alzheimer Mice. A Model to Study Early Tau Hyperphosphorylation Using Okadaic Acid

“…Amongst others, it particularly leads to the activation of GSK-3β, neuroinflammation and oxidative stress (Tachibana et al, 1981 ; Hanger et al, 2009b ; Kamat et al, 2013a ; Kamat and Nath, 2015 ; Baker and Götz, 2016 ; Zhao et al, 2016 ). Several in vivo and in vitro studies showed that OA induces tau phosphorylation and is also able to enhance the neurotoxicity of Aβ (Ahn et al, 2016 ; Baker and Götz, 2016 ; Zhao et al, 2016 ). Kamat et al ( 2013b ) reported that intracerebroventricular administered OA into rats impaired memory in the morris water maze.…”

1-(2′,5′-Dihydroxyphenyl)-3-(2-fluoro-4-hydroxyphenyl)-1-propanone (RGM079): A Positive Allosteric Modulator of α7 Nicotinic Receptors with Analgesic and Neuroprotective Activity

“…21 Similarly, in a model of neuronal death induced by okadaic acid (OA) that reproduces the typical tau (τ) hyperphosphorylation of Alzheimer's disease, it has been described that this hyperphosphorylation of tau reduces the expression of nAChRs and enhances the neurotoxicity of β-amyloid peptide. 23 In agreement with this fact, the activation of both α7 and β2* nAChR afforded neuroprotection against OA-induced neurotoxicity. 24 Curiously, the promotion of the Ca 2+ entry through the α7 nAChR using an α7-selective positive allosteric modulator (PAM), PNU 120596, did not protect against this OA-evoked neurotoxicity.…”

Screening of tau protein kinase inhibitors in a tauopathy-relevant cell-based model of tau hyperphosphorylation and oligomerization

“…It has been reported that OA results in robust tau hyperphosphorylation at multiple pathological epitopes in animal and cell culture studies [ 56 , 58 , 59 , 106 – 108 ]. It is widely established that PP2A is the primary enzyme responsible for dephosphorylation of tau protein throughout the brain, controlling all tau phosphorylation sites.…”